In modern medical practice, numerous implantable devices or prostheses are formed wholly or partially of biological tissue which has been chemically "fixed" or preserved. The technique used for chemical fixation of biological tissues typically requires exposure of the biological tissue to one or more chemical agents which are capable of forming cross-linkages between connective tissue protein molecules present in the tissue.
Examples of fixed biological tissues which have been used as bioprostheses include cardiac valves, blood vessels, skin, dura mater, pericardium, ligaments and tendons. These tissues typically contain a matrix of connective tissue proteins which act as the supportive framework of the tissue.
Collagen and elastin are two connective tissue proteins which make up the connective tissue framework of most biological tissues. The pliability or rigidity of each biological tissue is largely determined by its relative amounts of collagen and elastin and/or by the physical structure and confirmation of its connective tissue frame work.
Each collagen molecule is made up of three (3) polypeptide chains intertwined in a coiled helical confirmation. The chemical fixatives (i.e., tanning agents) which are used to preserve biological tissues generally form chemical cross-linkages between the polypeptide chains within a given collagen molecule (i.e., intramolecular crosslinkages), or between adjacent collagen molecules (i.e., intermolecular crosslinkages).
Examples of chemical fixative agents which have been utilized to crosslink collagenous biological tissues include; formaldehyde, glutaraldehyde, dialdehyde starch, hexamethylene diisocyanate and certain polyepoxy compounds. Of the various chemical fixatives available, glutaraldehyde is the most widely used. Glutaraldehyde is used as the fixative for many commercially available bioprosthetic products, such as porcine bioprosthetic heart valves (i.e., the Carpentier-Edwards.RTM. stented porcine bioprosthesis; Baxter Healthcare Corporation; Edwards CVS Division, Irvine, Calif. 92714-5686), bovine pericardial heart valve prostheses (e.g., Carpentier-Edwards.RTM. Pericardial Bioprosthesis, Baxter Healthcare Corporation, Edwards CVS Division; Irvine, Calif. 92714-5686) and stentless porcine aortic prostheses (e.g., Edwards.RTM. PRIMA.TM. Stentless Aortic Bioprosthesis, Baxter Edwards AG, Spierstrasse 5, GH6048, Horn, Switzerland).
One problem associated with the implantation of bioprosthetic materials is that the connective tissue proteins within these materials tend to undergo calcification. Such calcification can result in undesirable stiffening or degradation of the bioprosthesis. Both intrinsic and extrinsic calcification are known to occur in fixed collagenous bioprostheses, although the exact mechanism(s) by which such calcification occurs is unknown.
Clinical experience and experimental data has taught that glutaraldehyde-fixed collagenous bioprostheses may tend to calcify sooner than bioprostheses which have been fixed by other nonaldehyde fixative agents. Such accelerated calcification of glutaraldehyde-fixed bioprostheses has been reported to predominantly occur in pediatric patients. (Carpentier et al., Continuing Improvements in Valvular Bioprostheses, J. Thoracic Cardiovasc. Surg. 83:27-42, 1982.) Such accelerated calcification is undesirable in that it may lead to deterioration and/or failure of the implanted bioprostheses. In view of this propensity for accelerated calcification of glutaraldehyde-fixed bioprostheses in young patients, surgeons typically opt to implant mechanical heart valves or homografts (if available) into pediatric or relatively young patients (i.e., patients under 65 years of age), rather than glutaraldehyde-fixed bioprosthetic valves. However, patients who receive mechanical valve implants require ongoing treatment with anticoagulant medications, which can be associated with increased risk of hemorrhage. Also, homografts are of limited availability and may carry pathogens which can result in infection.
The factors which determine the rate at which glutaraldehyde-fixed bioprosthetic grafts undergo calcification have not been fully elucidated. However, factors which are thought to influence the rate of calcification include:
a) patient's age; PA1 b) existing metabolic disorders (i.e., hypercalcemia, diabetes, etc.); PA1 c) dietary factors; PA1 d) race; PA1 e) infection; PA1 f) parenteral calcium administration; PA1 g) dehydration; PA1 h) distortion/mechanical factors; PA1 i) inadequate coagulation therapy during initial period following surgical implantation; and PA1 j) host tissue responses. PA1 a. preparing a biological tissue which contains connective tissue proteins; PA1 b. contacting the biological tissue with an aldehyde fixative (e.g., formaldehyde or glutaraldehyde) to effect crosslinking of the connective tissue proteins within the tissue; and PA1 c. concurrently with, or after, the completion of step (b), contacting the tissue with a polyglycidyl ether. PA1 (a) preparing a biological tissue which contains connective tissue proteins; PA1 (b) contacting the biological tissue with an aldehyde fixative, such as glutaraldehyde, to effect crosslinking of the connective tissue proteins within the tissue; and PA1 (c) concurrently with or after the completion of step (b), contacting the tissue with a polyglycidyl ether.
Many investigators have attempted to discover ways of mitigating the in situ calcification of glutaraldehyde-fixed bioprostheses. Included among these calcification mitigating techniques are the methods described in U.S. Pat. No. 4,885,005 (Nashef et al.) entitled Surfactant Treatment of Implantable Biological Tissue To Inhibit Calcification; U.S. Pat. No. 4,648,881 (Carpentier et al.) entitled Implantable Biological Tissue and Process For Preparation Thereof; U.S. Pat. No. 4,976,733 (Girardot) entitled Prevention of Prosthesis Calcification; U.S. Pat. No. 4,120,649 (Schechter) entitled Transplants; U.S. Pat. No. 5,002,2566 (Carpentier) entitled Calcification Mitigation of Bioprosthetic Implants; EP 103947A2 (Pollock et al.) entitled Method For Inhibiting Mineralization of Natural Tissue During Implantation and WO84/01879 (Nashef et al.) entitled Surfactant Treatment of Implantable Biological Tissue to Inhibit Calcification; and, in Yi, D., Liu, W., Yang, J., Wang, B., Dong, G., and Tan, H.; Study of Calcification Mechanism and Anti-calcification On Cardiac Bioprostheses Pgs. 17-22, Proceedings of Chinese Tissue Valve Conference, Beijing, China, June 1995.
Because none of the previously known calcification mitigation, technique has proven to be optimal for glutaraldehyde-fixed tissues. There exists a need in the art for the development of new methods for inhibiting or mitigating calcification of glutaraldehyde-fixed biological tissues.